CrossTalk opposing view: CNNM proteins are not Na+/Mg2+ exchangers but Mg2+ transport regulators playing a central role in transepithelial Mg2+ (re)absorption

Magnesium (Mg2+) is indispensable for many physiological processes in the cell impacting organ function (de Baaij et al. 2015). Intracellular concentrations of free Mg2+ aremaintained within a narrow range (0.5–1.2 mM) through tightly regulated Mg2+ influx and effluxmechanisms (Ebel & Gunther, 1980). InhibitionofMg2+ effluxby substitution of extracellular Na+ by choline in mammalian cells indicates that Mg2+ extrusion is Na+ dependent (Guther et al. 1984). Thus, it is postulated that Mg2+ efflux occurs via a Na+/Mg2+ exchanger, this notion being corroborated in a large number of studies in different cell models (Romani, 2007). Under the premise that differential gene expression is involved in the maintenance of cellular Mg2+ homeostasis, microarray analyses in epithelial cells exposed to low extracellular Mg2+ concentrations have been classically used to designate proteins involved in Mg2+ transport (Quamme, 2010). One of the protein families identified with this approach is the CNNM family. CNNM proteins have been proposed to